Program Summary / Abstract HIV infection results in well-documented changes to gut-associated lymphoid tissue, but few studies have evaluated whether similar mucosal immunological dysfunction occurs in the oral cavity. Moreover, despite growing evidence of the importance of the microbiome in maintaining health and local homeostasis, the impacts of HIV on oral microbial communities and the mechanisms contributing to immunodeficiency-induced periodontitis and systemic inflammation remain poorly defined. Studies of these phenomena have been hampered by lack of a suitable animal model, as commonly used animal models for HIV (SIV/SHIV infections of non-human primates and HIV infections in humanized mice) do not reliably result in oral disease. Feline immunodeficiency virus (FIV) is a T cell tropic lentivirus that causes AIDS in its natural host, and results in immunological dysfunctions and opportunistic infections similar to HIV-AIDS. Relevant to this proposal, and similar to HIV infections, periodontal and oral inflammatory disease occurs in the majority of FIV-infected animals. Our preliminary studies demonstrate that FIV infection of domestic cats is associated with: (1) oral dysbiosis, with a marked loss of microbial diversity during FIV-associated periodontitis; and, (2) changes in salivary cytokine levels, even in the absence of FIV clinical oral disease. Furthermore, an easily administered cART protocol efficacious against SIV in macaques strongly inhibits FIV growth in vitro. Development of a well- tolerated, effective cART is an important next step in developing the FIV in vivo model for follow-on studies of HIV disease. We therefore propose to validate FIV as a relevant model for HIV-associated oral disease by assessing stepwise pathology that occurs in the presence and absence of FIV viral replication. We will monitor clinical status, oral microbiota, local and systemic viral burden, and immune profile during systemic treatment in the presence and absence of a novel cART therapy. Aim 1 will assess the impact of cART in controlling oral cavity viral replication and subsequent impacts on oral microbiome and local inflammation during acute and subacute infection. Aim 2 will apply causal modeling (Structural Equation Modeling) and model selection to determine the direct and indirect mechanistic basis of FIV-induced periodontal disease in the presence and absence of cART. We have assembled an experienced team of investigators to conduct the proposed experiments and modeling, and will work with experts in HIV oral disease to translate our findings into hypothesis-based approaches for new therapeutic interventions for HIV-associated oral disease. Further our work will interrogate local and systemic immune deficits related to oral cavity viral replication and infection.